1. Field of the Invention
The present invention provides novel compounds comprising a urea derivative, a linker, and a metal chelating group. The invention provides for novel radiolabeled compounds comprising a urea derivative, a linker, a metal chelating group, and a radiolabeled or isotopically labeled metal. This invention also provides pharmaceutical compositions comprising such radiolabeled compounds. Additionally, this invention provides methods of detecting biodistribution and imaging methods of the compounds of the invention which bind to PSMA and PSMA expressing tumors. The compounds of the invention are useful for providing an earlier diagnosis of cancers, imaging tumor angiogenesis, improved delineation of tumor margins during tumor surgery, and improvements in small molecule delivery of therapeutic radionuclides to cancer.
2. Background
Prostate cancer (PCa) is the leading cancer in the US population and the second leading cause of cancer-related death in men. By the time of diagnosis only one half of PCa tumors are clinically localized and one half of those represent extracapsular spread. Currently anatomic methods, such as computed tomography (CT), magnetic resonance (MR) imaging and ultrasound, predominate for clinical imaging of prostate cancer. The radiolabeled monoclonal antibody [111In]ProstaScint™ has also been used, however this agent tends to produce images that are challenging to interpret (Lange, P. H. PROSTASCINT scan for staging prostate cancer. Urology 2001, 57, 402-406; Haseman, M. K.; et al. Cancer Biother Radiopharm 2000, 15, 131-140; Rosenthal, S. A.; et al. Tech Urol 2001, 7, 27-37). Low molecular weight, radiopharmaceutical-based imaging agents may provide superior pharmacokinetics for imaging than radiolabeled antibodies, which tend to have long circulation times and delayed clearance from nontarget tissues. A variety of experimental low molecular weight PCa imaging agents are currently being pursued clinically, including radiolabeled choline analogs [18F]fluorodihydrotestosterone ([18F]FDHT), anti-1-amino-3-[18F]fluorocyclobutyl-1-carboxylic acid (anti[18F]F-FACBC), [11C]acetate and 1-(2-deoxy-2-[18F]fluoro-L-arabinofuranosyl)-5-methyluracil ([18F]FMAU) (Scher, B.; et al. Eur J Nucl Med Mol Imaging 2007, 34, 45-53; Rinnab, L.; et al. BJU Int 2007, 100, 786-793; Reske, S. N.; et al. J Nucl Med 2006, 47, 1249-1254; Zophel, K.; Kotzerke, J. Eur J Nucl Med Mol Imaging 2004, 31, 756-759; Vees, H.; et al. BJU Int 2007, 99, 1415-1420; Larson, S. M.; et al. J Nucl Med 2004, 45, 366-373; Schuster, D. M.; et al. J Nucl Med 2007, 48, 56-63; Tehrani, O. S.; et al. J Nucl Med 2007, 48, 1436-1441).
Each operates by a different mechanism and has certain advantages, e.g., low urinary excretion for [11C]choline, and disadvantages, such as the short physical half-life of positron-emitting radionuclides. A promising new series of low molecular weight imaging agents targets the prostate-specific membrane antigen (PSMA) (Mease R. C. et al. Clin Cancer Res. 2008, 14, 3036-3043; Foss, C. A.; et al. Clin Cancer Res 2005, 11, 4022-4028; Pomper, M. G.; et al. Mol Imaging 2002, 1, 96-101; Zhou, J.; et al. Nat Rev Drug Discov 2005, 4, 1015-1026).
PSMA is a type II integral membrane protein that has abundant and restricted expression on the surface of PCa, particularly in androgen-independent, advanced and metastatic disease (Schulke, N.; et al. Proc Natl Acad Sci USA 2003, 100, 12590-12595). The latter is important since almost all PCa becomes androgen independent. It is also expressed within the endothelium of most solid tumors other than prostate (Chang, S. S.; et al. Cancer Res 1999, 59, 3192-3198). PSMA possesses the criteria of a promising target for therapy, i.e., abundant and restricted (to prostate) expression at all stages of the disease, presentation at the cell surface but not shed into the circulation, and association with enzymatic or signaling activity (Schulke, N.; et al. Proc Natl Acad Sci USA 2003, 100, 12590-12595). The PSMA gene is located on the short arm of chromosome 11 and functions both as a folate hydrolase and neuropeptidase. It is the neuropeptidase function that is equivalent to glutamate carboxypeptidase II (GCPII), which is referred to as the “brain PSMA”, and may modulate glutamatergic transmission by cleaving N-acetylaspartylglutamate (NAAG) to N-acetylaspartate (NAA) and glutamate (Nan, F.; et al. J Med Chem 2000, 43, 772-774). There are up to 106 PSMA molecules per cancer cell, further suggesting it as an ideal target for imaging and therapy with radionuclide-based techniques (Tasch, J.; et al. Crit Rev Immunol 2001, 21, 249-261).
Recently selective imaging was demonstrated of xenografts that express PSMA using small animal positron emission tomography (PET) and single photon emission computed tomography (SPECT) and the urea-based PSMA inhibitors N—[N—[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)—[11C]methyl-L-cysteine, [11C]DCMC, N—[N—[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-3-[125I]iodo-L-tyrosine, [125I]DCIT and N—[N—[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-4-[18F]fluorobenzyl-L-cysteine, [18F]DCFBC (Mease R. C. et al. Clin Cancer Res. 2008, 14, 3036-3043; Foss, C. A.; et al. Clin Cancer Res 2005, 11, 4022-4028; Pomper, M. G.; et al. Mol Imaging 2002, 1, 96-101).
Although positron-emitting radionuclides are increasingly used in clinical medicine, 99mTc remains the radionuclide of choice for clinical scintigraphic imaging because of its favorable physical properties (t1/2=6 h, Eγ=140 keV), low cost and widespread availability. The development of technetium complexes as radiopharmaceuticals is facilitated by the use of rhenium, the group VIIB congener of technetium. Rhenium generally produces complexes with similar physical properties to those of technetium and is often used as a nonradioactive alternative to technetium for large-scale synthesis and structural characterization.
What is desired is to provide low molecular weight, urea-based inhibitors incorporating tridentate chelators for binding of the {M(CO)3}+ core, (M=99mTc, 186, 188Re), while retaining high affinity to PSMA. Because of high stability and favorable labeling characteristics, the organometallic Re(I)(CO)3/99mTc(I)(CO)3 approach represents an attractive radiolabeling strategy. A number of tridentate chelates with different sets of nitrogen, sulfur, oxygen donor atoms are known to form highly stable complexes with the {M(CO)3}+ cores (Alberto, R.; et al. J Am Chem Soc 1998, 120, 7987-7988; Alberto, R.; et al. J Am Chem Soc 2001, 123, 3135-3136). Among them, the single amino acid chelate concept (Banerjee, S. R.; et al. Nucl Med Biol 2005, 32, 1-20; Stephenson, K. A.; et al. Bioconjug Chem 2005, 16, 1189-1195), (SAAC), has proved useful for designing new urea-based inhibitors.